Neuroscience Forefront ReviewNeurogenesis along the septo-temporal axis of the hippocampus: Are depression and the action of antidepressants region-specific?
Introduction
In the last decade, research about major depressive disorder (MDD) and antidepressant therapy (ADT) has largely focused on adult hippocampal neurogenesis. Adult neurogenesis is the process by which new neurons are generated during adulthood from neural progenitors that first proliferate, and then differentiate into immature neurons which become functional once they have established connections with efficient inputs and outputs (maturation). Some of them do not integrate into the functional network and thus undergo apoptosis, while others survive (survival). Rodent studies have shown that a large number of factors associated with increased risk of MDD, such as unpredictable stress (Alonso et al., 2004, Mineur et al., 2007), elevated glucocorticoids (Mayer et al., 2006, Wong and Herbert, 2006, Brummelte and Galea, 2010, Hu et al., 2012) or aging (Kuhn et al., 1996, Bondolfi et al., 2004, Heine et al., 2004, Rao et al., 2006) decrease adult hippocampal neurogenesis. On the other hand, factors linked to recovery, including chronic ADT (Malberg et al., 2000; for reviews: Tanti and Belzung, 2010, Eisch and Petrik, 2012, Petrik et al., 2012), electroconvulsive therapy (Malberg et al., 2000), vagal nerve stimulation (Revesz et al., 2008), physical exercise (Van Praag et al., 1999, Fabel and Kempermann, 2008) and environmental enrichment (Kempermann et al., 1997, Veena et al., 2009, Schloesser et al., 2010) have the opposite effect. This has been confirmed in clinical findings, whereby adult hippocampal neurogenesis and/or progenitor cells have been shown to decrease in patients with MDD and to increase after ADT (Boldrini et al., 2009, Boldrini et al., 2012, Lucassen et al., 2010), even though contradictory findings have been described in a study not controlling for age or for medication used by MDD patients (Reif et al., 2006). Moreover, the participation of hippocampal new neurons seems mandatory for effective ADT, as a lack of adult hippocampal neurogenesis suppresses the effectiveness of ADT in animal MDD models (Santarelli et al., 2003, Perera et al., 2011, Surget et al., 2011), although this does not appear to be pivotal for all ADT-related effects (David et al., 2009). Despite the failure of some research to reproduce the latter findings (Bessa et al., 2009), a consensus has now been reached regarding the contribution of new dentate gyrus neurons in the ability of ADT to achieve remission. On the other hand, evidence suggesting a causal participation of adult hippocampal neurogenesis in the onset of MDD-related symptoms is much debated, and has produced contradictory findings (Santarelli et al., 2003, Snyder et al., 2011). All this research has elicited much interest and enthusiasm, as it provides a very simple view of the illness and of the mechanisms enabling recovery. It should, however, be considered with care, not only because some studies have failed to replicate the initial findings, but also because few attempts have been made to understand how the lack of adult newborn hippocampal neurons can precipitate a pathology such as MDD, or participate in recovery after ADT. MDD is indeed related to a complex symptomatology including cognitive (negative bias and deficits in executive functions) and emotional alterations (sadness and anhedonia), which are mostly linked to extra-hippocampal targets (sadness linked to the cingulate cortex and anhedonia to the nucleus accumbens) (see Berton and Nestler, 2006, Krishnan and Nestler, 2008, Price and Drevets, 2010, Price and Drevets, 2012, Disner et al., 2011, Russo et al., 2012 for reviews). This raises the question of how adult hippocampal neurogenesis could be involved in behavioral alterations related to these extra-hippocampal structures. An alternative hypothesis postulates that adult neurogenesis is not essential for recovery from all phenotypes associated with MDD, but only from some of them (David et al., 2009). Using X-irradiation in a mouse model, this study showed that ablation of adult neurogenesis in the dentate gyrus blocked effects related to chronic ADT (novelty suppression of feeding), but not the effects of fluoxetine less relevant for depression, such as those measured in an anxiety test (openfield) or in the Forced Swimming test. Although adult neurogenesis could be involved in specific aspects of the pathology, the particular function of the new hippocampal neurons necessary for the mechanism underlying ADT effects remains to be determined.
Section snippets
Functional dissociation along the septo-temporal axis of the hippocampus
The hippocampus is a heterogeneous brain area that, in rodents, extends both rostro-caudally and dorso-ventrally from the septal nuclei of the basal forebrain to the temporal lobe (Fig. 1). Along this septo-temporal axis a functional dissociation has been consistently described. For example, it is well established that a lesion in the hippocampus deteriorates the animal’s performance in a spatial navigation task, the Morris water maze (Morris et al., 1982). However, when the lesion spares the
Regional changes in adult neurogenesis along the septo-temporal axis of the hippocampus in animal models of depressive-like behavior
Table 1 provides a summary of publications addressing the regulation of adult neurogenesis along the septo-temporal axis of the hippocampus through behavioral, pharmacological and genetic models of depression. Studies investigating the effects of these factors only in the dorsal or ventral hippocampus have not been included. Regional effects of these models on cell proliferation, survival of adult newborn cells, maturation, differentiation and number of new neurons are detailed.
First, it is
Possible factors contributing to the differential effects of stress on septal and temporal neurogenesis
First, the amygdala, which modulates hippocampal activity (Ikegaya et al., 1996, Paz et al., 2006), contributes to the regulation of adult hippocampal neurogenesis and to the recruitment of adult newborn neurons in a fear eliciting context (Kirby et al., 2012). As the reciprocal hippocampal–amygdalar connections mainly originate from the ventral subiculum, it is thus possible that depressive and anxiety-like states affect adult neurogenesis preferentially in the ventral hippocampus.
Second,
Regional changes in adult neurogenesis along the septo-temporal axis of the hippocampus following chronic antidepressant therapy
Table 2 provides a list of the current publications addressing the regulation of adult neurogenesis along the septo-temporal axis of the hippocampus according to different classes of antidepressants in control animals or in animals exposed to different models of depressive-like behavior. Behavioral manipulations, such as physical exercise and environmental enrichment, which are known for both stimulating adult neurogenesis and exerting mood-improving or anxiolytic and also pro-cognitive
Effects of agomelatine
While most of the studies using SSRIs show uniform effects on adult neurogenesis along the septo-temporal axis of the hippocampus, the same pattern is not found in studies using the antidepressant agomelatine, which acts through a different mechanism than classic monoaminergic compounds (combining MT1/MT2 melatonergic receptor agonistic properties with a 5-HT2C receptor antagonist action). All five studies presented found that agomelatine had both region-specific effects and similar effects in
Differences in neurotransmission along the septo-temporal axis of the hippocampus
The differences in neurotransmission observed along the septo-temporal axis, in particular 5-HT transmission (Gage and Thompson, 1980), could also explain the distinct effects of ADT on adult neurogenesis between dorsal and ventral divisions of the hippocampus. 5-HT inputs to the dorsal hippocampus mainly originate from the medial raphe nucleus, whereas the ventral hippocampus receives 5-HT projections mainly from the dorsal raphe nucleus (Azmitia and Segal, 1978, Köhler and Steinbusch, 1982,
Environmental effects on neurogenesis in the septal and temporal hippocampus
An interesting approach to assess whether regulation of adult neurogenesis along the septo-temporal axis may be correlated to the functional specialization of the dorsal and ventral poles of the hippocampus is to investigate the effects of environmental factors involving the recruitment of dorsal hippocampal pathways. In accordance with its functional specialization, learning paradigms may have preferential effects in the dorsal hippocampus. A summary of such studies is shown in Table 3. Two
Discussion
Overall, this review of the literature suggests that animal models of depression are associated with impairments of adult neurogenesis, with a tendency for a preferential effect in the ventral hippocampus. ADT should therefore be expected to counteract the effects of models of depression, and thus to stimulate adult neurogenesis preferentially in the ventral sub-region. Surprisingly, this does not seem to be the case. Some studies tested the effects of selective serotonin reuptake inhibitors
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